Urinary clearance of noradrenaline in the dog]

Glomerular filtration rate (GFR) and noradrenaline clearance are highly correlated in anesthetized dogs (ratio CNA-3H/GFR approximately 1).     

Acute tolerance to noradrenaline ("noradrenaline escape")]

The decline in arterial systemic blood pressure which follows the initial rise during i.v. perfusion of L-noradrenaline in normal rats has been compared with the same type of decline induced by metaraminol or phenylephrine, both alpha-sympathomimetic drugs (acute tolerance or escape). Vasoconstrictor activity of noradrenaline in shot i.v. injection is regularly decreased when acute tolerance develops. This hyposensitivity to NA indicates that a change in alpha-receptor affinity for circulating NA may explain the acute tolerance as well as the noradrenaline escape.     

Differential alpha-mediated inhibition of dopamine and noradrenaline release in the parietal and occipital cortex following noradrenaline transporter blockade

Parietal and occipital cortices, while densely innervated by noradrenalin 2 (NA) projections, possess a comparatively sparse dopamine 2 (DA) innervation, even sparser than the prefrontal cortex. We previously reported that reboxetine and desipramine, two selective norepinephrine transporter (NET) blockers, at doses that maximally increase DA in the prefrontal cortex, do not increase DA in the parietal and occipital cortices. In the present study, we performed a full dose-response study of the effect of systemic reboxetine and desipramine on DA and NA in dialysates from the parietal and occipital cortices. Seven doses of reboxetine (0.1, 0.25, 0.5, 1.0, 2.5, 5.0 and 10 mg/kg) and four doses of desipramine (0.25, 1.0, 2.5 and 5.0 mg/kg) were tested. Reboxetine and desipramine differentially affected dialysate DA as compared with NA. Reboxetine increased DA maximally by about 100% after doses of 0.25-0.5 mg/kg and showed a bell-shaped dose-response function in both areas; desipramine did not affect DA in the parietal cortex and increased it in the occipital cortex only at 2.5 mg/kg. NA was maximally increased by 275% by 0.5-2.5 mg/kg reboxetine and by about 300% by 5.0 mg/kg desipramine with a more linear dose-response curve. The mechanism of peculiar dose-response function of dialysate DA after reboxetine and desipramine was further investigated by testing the effect of drugs on dialysate DA and NA under alpha(2) receptor blockade. Under local perfusion of the occipital cortex with idazoxan, an otherwise ineffective dose of reboxetine and desipramine (5 mg/kg) became effective in raising extracellular DA. In contrast, the effect of reboxetine on NA was potentiated, while that of desipramine was not affected. These results suggest that, in the parietal and occipital cortices, extracellular NA, raised by NET blockade, exerts a preferential inhibitory influence on DA release by acting on local alpha(2) receptors, thus accounting for the bell-shaped feature of the dose-response function of drugs on dialysate DA in these areas.     

去甲肾上腺素在脊髓背角的镇痛机制

疹髓背角浅层是传递和调制外周伤害性信息的关键部位。起源于脑干的去甲肾上腺素（NA）能纤维终止脊髓背角,它们释放的NA具有抑制初级传入末梢释放谷氨酸和P物质、增加Ⅱ层（胶状质）抑制性神经活性物质释放的作用。此外,形态学研究提示NA可能直接抑制Ⅰ/Ⅲ层向丘脑传递伤害性信息的投射神经元。NA可能通过以上途径,实现对外周伤害性信息传递的调制而发挥镇痛作用。     

Involvement of D1 dopamine receptors in the nicotine-induced noradrenaline release from hypothalamic and preoptic noradrenaline nerve terminal systems

Nicotine (4 × 2 mg/kg, i.p.) was given every 30 min for 2 h to male rats. Some rats were pretreated with the D1 dopamine (DA) receptor antagonist SCH 23390 (1 mg/kg, i.p.) or with the D2 DA receptor antagonist raclopride (1 mg/kg, i.p.), 5 min before nicotine treatment. Hypothalamic and preoptic catecholamine levels were measured by quantitative histofluorimetry in discrete DA and noradrenaline nerve terminal systems.Nicotine treatment produced a depletion of catecholamine stores in noradrenaline and DA nerve terminals of the hypothalamus, the preoptic area and the median eminence, an action which was counteracted by SCH 23390 but not by raclopride.The results indicate that hypothalamic D1 DA receptors may regulate the sensitivity of the nicotinic cholinoceptors and increase their ability to release hypothalamic noradrenaline. A possible role of D1 DA receptor antagonists to reduce the ability of nicotine treatment to produce rapid increases in LH, prolactin and corticosterone secretion and tonic arousal is implicated.     

Enhanced sensitivity to noradrenaline of the Ainu

A small dose of noradrenaline, which was ineffective in non-Ainu Japanese subjects, caused marked elevations in energy metabolism and plasma levels of FFA and total ketone bodies in the Ainu. The striking sensitivity to noradrenaline of the Ainu is assumed to indicate a characteristic feature of cold adaptability of this ethnic group.

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Zusammenfassung Eine geringe Dosis Noradrenalin, die bei nicht-Ainu Japanern unwirksam war, bewirkte bei Ainus eine ausgeprägte Erhöhung des Stoffwechsels, des Plasmaspiegels, der freien Fettsäuren und der Gesamt-Ketonkörper. Die Noradrenalin-Empfindlichkeit der Ainus wird als Kennzeichen besonderer Kälteanpassungsfähigkeit erklärt, das für diesen Volksstamm kennzeichend ist.

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Resume Une faible dose de noradrénaline, dose qui reste sans effet sur les Japonais n'appartenant pas à la race des Ainous, provoque au contraire une nette élévation du métabolisme énergétique chez les natifs de cette race. Cette élévation se signale notamment par le relèvement du taux des acides gras libres et des masses de kétone dans le sérum sanguin. L'extrême sensibilité des Ainous à la noradrénaline explique la facilité avec laquelle les gens de cette race s'adaptent au froid. Cette facilité d'adaptation est d'ailleurs une des caractéristiques de cette race.

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This study was made as a part of J-IBP/HA.     

Marked dissociation between high noradrenaline versus low noradrenaline transporter levels in human nucleus accumbens

We recently identified a noradrenaline-rich caudomedial subdivision of the human nucleus accumbens (NACS), implying a special function for noradrenaline in this basal forebrain area involved in motivation and reward. To establish whether the NACS, as would be expected, contains similarly high levels of other noradrenergic markers, we measured dopamine-beta-hydroxylase (DBH) and noradrenaline transporter in the accumbens and, for comparison, in 23 other brain regions in autopsied human brains by immunoblotting. Although the caudomedial NACS had high DBH levels similar to those in other noradrenaline-rich areas, the noradrenaline transporter concentration was low (only 11% of that in hypothalamus). Within the accumbens, transporter concentration in the caudal portion was only slightly (by 30%) higher than that in the rostral subdivisions despite sharply increasing rostrocaudal gradients of noradrenaline (15-fold) and DBH. In contrast, the rostrocaudal gradient in the accumbens for the serotonin transporter and serotonin were similar (2-fold increase). The caudomedial NACS thus appears to represent the only instance in human brain having a striking mismatch in high levels of a monoamine neurotransmitter versus low levels of its uptake transporter. This suggests that noradrenaline signalling is much less spatially and temporally restricted in the caudomedial accumbens than in other noradrenaline-rich brain areas.